Most pharmacologically active substances may be used for bringing about effects incompatible with their originally intended usage. In short, pharmacologically active substances such as narcotic analgesics, opioid analgesics or psychotropics for use in cancer pain are abused or wrongfully used, and not properly used for the treatment of diseases. For example, opioids which are highly effective for controlling severe pain are often abused to induce a state of high similar to drunkenness. In the worst case, persons who have abused opioid may die as a result.
Persons who attempt to abuse a pharmacologically active substance (abusers) employ various methods in order to be able to abuse the substance. For example, abusers can obtain the desired result, i.e., a drunk-like high, by ingesting a powder obtained by the crushing or grinding of tablets or capsules through the mouth or by snorting the powder through the nose. Alternatively, abusers extract a pharmacologically active substance via an aqueous liquid from a powder obtained by the grinding of tablets or capsules and can obtain a drunk-like high by parenterally, particularly, intravenously, administering the obtained solution. In an alternative possible approach, abusers extract a pharmacologically active substance not only into ethanol but into various organic solvents, then dissolve, in an aqueous liquid, a powder after evaporating the organic solvent and then inject the resulting solution, or directly snort the powder through the nose.
The abuse of pharmacologically active substances is now becoming a very serious social problem in the United States. The Food and Drug Administration (FDA) issued Abuse-Deterrent Opioids—Evaluation and Labeling as Guidance for Industry in April 2015 in order to prevent the abuse of pharmaceutical products. This guidance describes various approaches for avoiding drug abuse.
For example, it has been proposed that formulations containing a harmful agent or antagonist in addition to a pharmacologically active substance are designed to bring about unpleasant effects or antagonistic effects only when misapplied. Another example includes the avoidance of drug abuse by enhancing the mechanical properties, particularly, mechanical strength, of formulations. The main advantage of such formulations is that it is impossible to crush the formulations into powder by ordinary means used by abusers, for example, grinding in a mortar or pulverization using a hammer, or the formulations are at least unable to be injected or are substantially hindered from being snorted through the nose.
The challenge for extended-release formulations containing opioids is to render the formulations unable to be pulverized for abuse but to produce adequate therapeutic effects when properly used. According to WO2006/002884 (Patent Literature 1), it has been found that an extended-release formulation containing opioids, a synthetic or natural polymer and wax has a fracture resistance (mechanical strength) that renders the formulation unable to be pulverized. According to this invention, the mechanical strength of the extended-release formulation produced through the use of the properties of the polymer (polyethylene oxide) is too large for abusers to be able to pulverize the formulation. Thus, it is impossible for abusers to chew up and swallow the formulation or to snort the formulation through the nose. In addition, the polymer (polyethylene oxide) used has a property of exhibiting a high viscosity upon contact with water. Therefore, abusers cannot inject the solution because the solution cannot be aspirated into a syringe.
Formulations that must resist being abused are not limited to the extended-release formulations. In short, the challenge for attempts to obtain analgesic effects especially rapidly by proper use is that immediate release of the pharmacologically active substance is required. WO2013/017242 (Patent Literature 2) discloses an invention relating to an abuse deterrent formulation comprising a matrix material and a plurality of particulates, the particulates comprising a pharmacologically active substance and a polyalkylene oxide, wherein the particulates are embedded in the matrix material to form a discontinuous phase. According to this invention, rapid pharmacological effects are expected because the pharmacologically active substance is immediately released from the formulation. Furthermore, snorting is impossible because the particulates have adequate mechanical strength and are thus not pulverized. In addition, the polymer (polyethylene oxide) used has a property of exhibiting a high viscosity upon contact with water. Therefore, abusers cannot inject the solution because the solution cannot be aspirated into a syringe.
Likewise, according to National Publication of International Patent Application No. 2008-520634 (Patent Literature 3), granules comprising thickener-containing fine particles supplemented with a wax having a low melting point have a property of exhibiting a high viscosity upon contact with water. Therefore, abusers cannot inject the solution. Furthermore, the granules become a paste even if pulverized. Therefore, abusers cannot snort the paste through the nose.
National Publication of International Patent Application No. 2009-537456 (Patent Literature 4) discloses an invention relating to an extended-release formulation in which granules containing a pharmacologically active substance are provided with a coating for controlling the release of the pharmacologically active substance and coexist with a thickener and an ion-exchange resin. According to this invention, the dissolution behavior of the pharmacologically active substance does not change between before and after pulverization even if the granules are pulverized. Thus, the thickener and the ion-exchange resin can prevent the pharmacologically active substance in the granules from being liberated into water, alcoholic drinks or nonalcoholic drinks.
However, these preceding techniques are not satisfactory in terms of the following points.
In WO2006/002884 (Patent Literature 1), the manufacture of an extended-release formulation having adequate mechanical strength requires special manufacturing apparatus because of the properties of polyethylene oxide used. Therefore, this approach is not versatile. Polyethylene oxide, which is commonly used in WO2006/002884 (Patent Literature 1) and WO2013/017242 (Patent Literature 2), produces tablets or granules having mechanical strength (flexibility) by the application of a temperature equal to or higher than the softening point because of its material properties and can provide a formulation having abuse deterrent properties. However, polyethylene oxide is a heat-labile substance in the first place. Thus, not only is polyethylene oxide itself decomposed thereby decreasing its functions, but the decomposition product reacts compositely with the pharmacologically active substance so that the pharmacologically active substance is decomposed (Non-patent Literatures 1 and 2). Therefore, a manufacturing method using a heating process (hot melt extrusion method) is not always the best method.
In the case of adopting the hot melt extrusion method, a stabilizer such as α-tocopherol or dibutylhydroxytoluene may be used for stabilizing polyethylene oxide. However, the cost and time for development are increased because the appropriate amount and safety of the stabilizer, the stability of the pharmaceutical product, and the influence on pharmaceutical additives having other functions are to be confirmed (Non-patent Literatures 3 and 4).
National Publication of International Patent Application No. 2008-520634 (Patent Literature 3) does not specifically disclose a release rate related to effectiveness or safety. Therefore, it is not certain that effectiveness or safety can be secured by proper use.
In an alternative possible approach of abuse, abusers employ not only ethanol but various organic solvents, particularly, in the extraction of pharmacologically active substances, then dissolve, in an aqueous liquid, a powder after evaporation of the organic solvents and inject the resulting solution, or directly snort the powder through the nose. Polyethylene oxide, which is used in WO2006/002884 (Patent Literature 1) and WO2013/017242 (Patent Literature 2), has a property of having affinity for water and exhibiting a high viscosity in water and is therefore a pharmaceutical additive suitable for the development of abuse deterrent formulations. However, extractability using organic solvents such as methanol is high for formulations produced by the hot melt extrusion method. Therefore, this approach lacks measures against the extraction of a pharmacologically active substance by abusers. The technique used in National Publication of International Patent Application No. 2009-537456 (Patent Literature 4) tempts abusers to extract a pharmacologically active substance using, for example, methanol or other organic solvents, and is thus not sufficient, because it is limited to water, ethanol, a mixed solvent thereof, and typically drinkable solutions, as solvents for extraction.